Abstract
Rheumatoid arthritis is a disease associated with painful joints that affects approximately 1% of the population worldwide, and for which no specific cure is available. Among other functions, the endoplasmic reticulum (ER) has an important role in protein folding. When the level of unfolded proteins in the ER exceeds the folding capacity of this organelle, defective proteins are eliminated by ER-associated degradation (ERAD), an ATP-dependent ubiquitin–proteasome degradation process, to reduce the burden on the ER. Synoviolin is an E3 ubiquitin ligase that is involved in ERAD. This protein is a pathogenic factor for arthropathy; it is overexpressed in the synovial cells of patients with rheumatoid arthritis. This overexpression results in a 'hyper-ERAD' state, in which the cell deals with accumulated unfolded proteins excessively. Rheumatoid synovial cells produce large amounts of various proteins such as cytokines and proteases, which consequently might confer an autonomous proliferation property on the cells. At least 30% of all newly synthesized, ER-sorted proteins are unfolded. Although degradation of unfolded proteins consumes large amounts of ATP and would seem an unconventional process, it is essential for joint homeostasis.
Key Points
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Synoviolin, an E3 ubiquitin ligase that is associated with endoplasmic reticulum-associated degradation (ERAD), is highly expressed in rheumatoid synovial cells and is involved in the onset of rheumatoid arthritis (RA)
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Synoviolin targets the tumor suppressor protein p53 for proteasomal degradation, and can regulate both ER-stress-induced and p53-dependent apoptotic pathways
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Rheumatoid synovial cells undergo autonomous proliferation and aberrant protein production caused by hyper-ERAD by overexpression of synoviolin
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Approximately 30% of newly synthesized proteins are unfolded; the cell utilizes ATP to degrade these proteins, which enables synovial cells to maintain a single-layer structure
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Acknowledgements
We thank N Okamoto, Fun-site, ITAKURA OFFICE and all members of Professor Nakajima's laboratory. This work was partially supported financially by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (Creative research conducted by university researchers individually or in groups Category A, Category C), Ministry of Health, Labour and Welfare Grants-in-Aid for Scientific Research (Research on Allergic disease and Immunology), the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (04-3), the Kanagawa Nanbyo Foundation, Heiwa Nakajima Foundation, The Uehara Memorial Foundation, Takeda Science Foundation, Mitsui Life Insurance Co. Ltd. and the Sagawa Foundation for Promotion of Cancer Research.
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Yagishita, N., Yamasaki, S., Nishioka, K. et al. Synoviolin, protein folding and the maintenance of joint homeostasis. Nat Rev Rheumatol 4, 91–97 (2008). https://doi.org/10.1038/ncprheum0699
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DOI: https://doi.org/10.1038/ncprheum0699
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